The primary focus of research efforts has been the work involved in the 5-year NIH grant (R29-46625) focused on the role of nicotinic mechanisms in dementia. We have recently completed a large series of studies on the Clinical Research Center using the nicotinic antagonist mecamylamine as a probe of the integrity of CNS nicotinic systems. We have shown that temporarily blocking nicotinic receptors produces cognitive impairment in young normal subjects and older normal individuals show enhanced sensitivity to the cognitive-impairing effects of nicotinic blockade, with a shift to the left in the dose response curve for mecamylamine. This supports our hypothesis that there is an age-related decline in the integrity of CNS nicotinic systems, as autopsy studies have suggested a decline in the number of nicotinic receptors. Results from our studies of Alzheimer's disease patients with mecamylamine suggest a futher enhancement of sensitivity, consistent with autopsy data showing a selective loss of CNS nicotinic receptors. These results suggest that the loss of CNS nicotinic receptors in aging and Alzheimer's disease has significant functional consequences, especially with respect to the acquisition of new information, working memory, and rapid information processing.